Hyaluronate-Based Self-Stabilized Nanoparticles for Immunosuppression Reversion and Immunochemotherapy in Osteosarcoma Treatment
Yi Zhang, Tao Yuan, Zuxi Li, Chunyang Luo, Yuxuan Wu, Jiyong Zhang, Xiao Zhang, Weimin Fan
Abstract
Immunotherapy is regarded as a potential strategy to combat cancer, especially when immunotherapy is combined with appropriate chemotherapy. However, the immunosuppressive tumor microenvironment (TME) and serious side effects extremely limit the application of immunotherapy. Herein, a self-stabilized hyaluronic acid nanoparticle is synthesized for tumor-targeted delivery of doxorubicin (DOX), cisplatin (CDDP), and resiquimod (R848) in osteosarcoma immunochemotherapy, which is referred to as CDDPNPDOX&R848. CDDPNPDOX&R848 exhibits sufficient stability, great pH responsibility, and brilliant tumor-targeting accumulation in vivo, which make it suitable for further in vivo applications. After intravenous injection, CDDPNPDOX&R848 can release the loaded cargoes under the acidic TME continuously. DOX can induce tumor cell apoptosis in combination with CDDP and trigger immunogenic cell death. More importantly, the immune-activated TME created by R848 can facilitate tumor-associated antigen presentation and antitumor immunity elicitation. Benefiting from the synergistic effect of chemotherapy and immunotherapy, the growth of tumors and lung metastasis was greatly inhibited by CDDPNPDOX&R848 in the K7M2 orthotopic osteosarcoma mouse model. Thus, this intelligent codelivery platform might be a competitive candidate for osteosarcoma immunochemotherapy.